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Polyamine Biosynthetic Metabolic Dys...

Rosario, Spencer.

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Polyamine Biosynthetic Metabolic Dysregulation: Targeting and the Adaptive Response.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Polyamine Biosynthetic Metabolic Dysregulation: Targeting and the Adaptive Response./
Author:	Rosario, Spencer.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	228 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
Contained By:	Dissertations Abstracts International81-12B.
Subject:	Oncology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27835463
ISBN:	9798635239360

Polyamine Biosynthetic Metabolic Dysregulation: Targeting and the Adaptive Response.
Rosario, Spencer.

Polyamine Biosynthetic Metabolic Dysregulation: Targeting and the Adaptive Response. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 228 p.

Source: Dissertations Abstracts International, Volume: 81-12, Section: B.

Thesis (Ph.D.)--State University of New York at Buffalo, 2020.

This item must not be sold to any third party vendors.

Despite a 98.9% 5-year survival rate for prostate cancer (PCa), 20-30% of individuals will recur after the 5-year mark and will ultimately develop lethal hormone refractory disease, also known as Androgen Deprivation Therapy-Resistant prostate cancer (ADT-RPCa). Research in the field has concentrated on the idea that resistance is due to changes along the androgen axis, and therefore better targeting of this axis will reduce recurrence or prolong clinical benefit of ADT. We offer a novel approach for identifying and leveraging metabolic stress unique to PCa as a way to complement attacks on the androgen axis, while working via mechanisms independent of that axis. We question how to both exploit metabolic changes for therapeutic benefit and circumvent potential resistance mechanisms, and believe understanding adaptive response to metabolic therapy is key. We previously developed a bioinformatics pipeline to determine which metabolic pathways are most dysregulated based on analysis of transcriptomic data in PCa, and identified the polyamine biosynthetic pathway as being highly uniquely dysregulated in prostate cancer. Consequently, our lab has shown successful selective targeting of the polyamine biosynthetic pathway and connected methionine salvage pathway in PCa both in vivo and in vitro. Treating with the polyamine analogue, N(1),N(11)-bis(ethyl)norspermine (BENSpm), and inhibition of the methionine salvage pathway (MSP) with the methylthioadenosine phosphorylase (MTAP) inhibitor Methylthio-DADMe-Immucillin-A (MTDIA) eliminates a highly protected mechanism by which prostate cells relieve metabolic strain caused by increased polyamine biosynthesis, albeit to varying sensitivities. Therefore, the overall objective of this research is to identify the adaptive response that arises when polyamine catabolism is activated along with inhibition of methionine salvage in prostate cancer. Further, we hypothesized that identification of a Master Metabolic Transcriptional Regulator of the response to therapy represents potential mediators of adaptation that can be exploited to stratify PCa patient populations that will be most responsive to the drug combination being proposed, while also identifying a population that would benefit from new strategies targeting the adaptive response. Preliminary findings implicate the MMTR, JAZF1, as crucial to metabolic reprogramming in PCa. We propose to determine the role of JAZF1 in regulating metabolism of PCa and determine how this may impact response to therapeutic intervention. This novel approach takes advantage of an inherent metabolic strain accentuated in prostatic epithelial cells and enhanced in PCa, in order to develop novel therapeutic strategies and expands upon it by understanding how PCa cells attempt to adapt to metabolic therapy-induced stress.

ISBN: 9798635239360Subjects--Topical Terms:

751006
Oncology.
Subjects--Index Terms:

Bioinformatics

Polyamine Biosynthetic Metabolic Dysregulation: Targeting and the Adaptive Response.
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520 $a Despite a 98.9% 5-year survival rate for prostate cancer (PCa), 20-30% of individuals will recur after the 5-year mark and will ultimately develop lethal hormone refractory disease, also known as Androgen Deprivation Therapy-Resistant prostate cancer (ADT-RPCa). Research in the field has concentrated on the idea that resistance is due to changes along the androgen axis, and therefore better targeting of this axis will reduce recurrence or prolong clinical benefit of ADT. We offer a novel approach for identifying and leveraging metabolic stress unique to PCa as a way to complement attacks on the androgen axis, while working via mechanisms independent of that axis. We question how to both exploit metabolic changes for therapeutic benefit and circumvent potential resistance mechanisms, and believe understanding adaptive response to metabolic therapy is key. We previously developed a bioinformatics pipeline to determine which metabolic pathways are most dysregulated based on analysis of transcriptomic data in PCa, and identified the polyamine biosynthetic pathway as being highly uniquely dysregulated in prostate cancer. Consequently, our lab has shown successful selective targeting of the polyamine biosynthetic pathway and connected methionine salvage pathway in PCa both in vivo and in vitro. Treating with the polyamine analogue, N(1),N(11)-bis(ethyl)norspermine (BENSpm), and inhibition of the methionine salvage pathway (MSP) with the methylthioadenosine phosphorylase (MTAP) inhibitor Methylthio-DADMe-Immucillin-A (MTDIA) eliminates a highly protected mechanism by which prostate cells relieve metabolic strain caused by increased polyamine biosynthesis, albeit to varying sensitivities. Therefore, the overall objective of this research is to identify the adaptive response that arises when polyamine catabolism is activated along with inhibition of methionine salvage in prostate cancer. Further, we hypothesized that identification of a Master Metabolic Transcriptional Regulator of the response to therapy represents potential mediators of adaptation that can be exploited to stratify PCa patient populations that will be most responsive to the drug combination being proposed, while also identifying a population that would benefit from new strategies targeting the adaptive response. Preliminary findings implicate the MMTR, JAZF1, as crucial to metabolic reprogramming in PCa. We propose to determine the role of JAZF1 in regulating metabolism of PCa and determine how this may impact response to therapeutic intervention. This novel approach takes advantage of an inherent metabolic strain accentuated in prostatic epithelial cells and enhanced in PCa, in order to develop novel therapeutic strategies and expands upon it by understanding how PCa cells attempt to adapt to metabolic therapy-induced stress.
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653 $a Methionine
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